HETEROGENEITY OF INTESTINAL METAPLASIA

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HETEROGENEITY OF INTESTINAL METAPLASIA - MUCIN HISTOCHEMISTRY

The fact that intestinal metaplasia (IM) is a common finding in both benign and malignant conditions and that its incidence increases with age, limits its potential value as an indicator of gastric cancer risk.
In this chapter we focus on the heterogeneity of IM as shown by morphological parameters of cell differentiation, crypt architecture and mucin histochemistry.
The importance of these classifications is based on retrospective and prospective studies in different populations which indicate a close association between certain subtypes of IM and the risk of gastric carcinoma.

**Histochemical Techniques and their Interpretation**
Method	Colour	Mucins
Diastase Periodic Schiff (D-PAS)	Magenta	- Neutral mucins and acid mucins - Some non-sulphated acid mucins (sialomucins)
Periodate-Borohydride /Saponification/PAS (PB/KOH/PAS)	Magenta	O-Acylated Borohydride/sialomucins
Alcian blue pH 2,5/PAS	Blue Magenta Purple-blue	- Acid mucins - Neutral mucins - Mixed neutral and acid mucins
High iron diamine/ Alcian blue pH 2,5 (HID/AB)	Brown Blue	- Sulphomucins - Non-sulphated acid mucins (sialomucins)

GASTROINTESTINAL MUCINS AND AGE

Throughout foetal life, gastric surface mucus is a mixture of sialomucins and neutral mucins with a gradual decrease of sialomucins and neutral mucins being predominant at 23 weeks, reaching an adult pattern at birth. O-acylated mucins and sulphomucins are not detected.

In the adult most of the gastrointestinal mucins contain sialic acid residues and sulphate groups, which may be present in the same glycoprotein molecule but in different oligosaccharide units.

VARIOUS CLASSIFICATIONS OF INTESTINAL METAPLASIA

Based on Mucin Histochemistry/Morphology/Differentiation Staining Techniques : (Alcian Blue/PAS and HID/AB)

•1A – Intestinal Metaplasia

Type 1 "Complete" : Straight crypts and regular architecture. Crypts are lined by mature columnar cells and goblet cells. Goblet cells secrete sialomucins and columnar cells are non-secretory and reveal a well-formed brush border. Paneth cells are often present.
Type 2 "Incomplete" : The crypts are elongated and tortuous and there is mild architectural distortion. Crypts are lined by columnar cells in various stages of differentiation secreting neutral mucins and/or small amounts of sialomucin. The goblet cells secrete sialo- and occasionally sulphomucin. Paneth cells are rarely observed.
Type 3 "Incomplete" : Distortion of crypt architecture is more pronounced and loss of differentiation and cellular atypia are more marked than in type 2. Columnar cells secrete predominantly sulphomucins and goblet cells contain sialo- and/or sulphomucins. Paneth cells are usually absent.

•1B – Simplified Version

HID/AB Staining : Blue = sialomucins; Brown = sulphomucins.

Type 1 (complete): Goblet cells = sialomucins + sulphomucins. Columnar cells = non-secretory.
Type 2 (incomplete): Goblet cells = sialomucins + sulphomucins. Columnar cells = sialomucins.
Type 3 (incomplete): Goblet cells = sialomucins + sulphomucins Columnar cells = sulphomucins.

•1C – Modified Classification of 1A (Applied to the cohort study of 1496 patients with IM in Slovenia)

Considering that the presence of sulphomucins is the main characteristic of IM type 3, the relative risk of gastric carcinoma was estimated according to the presence of sulphomucins in "intermediate columnar cells", in goblet cells and other cells (basal, neck region or foveolar).
IM types 1 and 2 : were subdivided with two groups :

(i) (reference group): Sulphomucin- in goblet cells and other cells,
(ii) Sulphomucin + in any other cells.

IM type 3 : classified into two groups according to :

(i) Sulphomucin- in goblet cells
(ii) Sulphomucin+ in goblet cells, columnar cells and other cells.

Compared with the reference group the RR for developing carcinoma was: 5.76 (95% CI: 2.11-15-73) for type 3 IM (ii)

Classification of intestinal metaplasia based on sialomucin acetylation sites (SAS)

In normal circumstances O-acylated sialic acids are secreted only in the epithelial cells of the lower Gl tract (ie caecum, colon or rectum) and not in the small intestine.

• Complete IM (type 1) :
Characterised by columnar cells (non-mucin-secreting) and goblet cells which often show strong dPAS positivity. Only a few are weakly positive and these show strong positivity with PB/KOH/PAS indicating O-acylated sialomucins. With HID/AB these goblet cells show predominance of sialomucins and occasional focal sulphomucins.
Thus complete IM resembles small intestine, thus sialomucins predominate including N-acetyl sialomucins, less amount of O-acylated sialomucins and rarely sulphomucins.

• Incomplete IM (type 2 or 3) :
Characterised by columnar mucous-secreting cells and goblet cells resembling colonic mucosa. Unlike complete IM no PB/KOH/PAS positive mucin was detected in the columnar cells or goblet cells in either type 2 or type 3 IM. This pattern is normally found in fetal gut, suggesting that O-acylation loss in incomplete IM may be related to a more immature type of epithelium similar to that found in fetal gut where O-acetylation has not yet taken place. It has also been interpreted as a phenotypic change related to one hostile microenvironment, impaired maturation or aberrant differentiation along ileal and colonic cell lines.

INTESTINAL MUCIN TYPES AND CLINICAL IMPLICATIONS

The relationship between gastric carcinoma and intestinal metaplasia of "incomplete type", "colonic type", type 3 showing incomplete differentiation and the presence of columnar cells and goblet cells secreting sulphomucins, has been assessed in various populations.

In a large cohort study it was shown that type 3 IM is closely associated with gastric carcinoma of intestinal type, and within IM it is a more selective indicator of cancer risk. Types I and II are prevalent in both benign and malignant conditions, and are thus not useful as markers of cancer risk.

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